Alzheimer's disease (AD) is a progressively dementing disorder characterized by the accumulation in the brain of pathogenic peptides largely comprised of amyloid-beta peptide (Ab), a derivative of the amyloid precursor protein (APP). Ab1-42, the predominant extracellular form, arises from cleavage of APP by two endoproteases, the 2- and 3- secretases, and undergoes assembly into oligomeric forms some of which are postulated to compromise synaptic function. Our laboratory is interested in understanding the early mechanisms that initiate or perpetuate this temporal and spatial progression of AD pathogenesis, and in exploiting an understanding of these mechanisms to derive novel therapeutics. One strategy to treat AD is to deplete the Ab within the parenchymal space and preclude formation of the putative damaging oligomeric forms. Several groups have been successful by introducing antibodies through either active or passive means, although many have incurred untoward immunological events. Among the approaches pursued we seek to deliver to the AD brain recombinant viral vectors that will express a human single chain fragment variable (scFv) antibody directed against Ab oligomeric forms with the goal of facilitating its clearance and preventing synaptic dysfunction and neuronal toxicity. We hypothesize that gene-based passive immunization using single-chain antibodies directed against oligomeric forms of Ab will prevent Ab-engendered synaptotoxicity and will diminish the downstream pathological events that include amyloid plaques, neurofibrillary tangle formation, and associated effects on neuronal viability. Recombinant adeno-associated virus (rAAV) vectors expressing the engineered antibodies will be administered to 3xTg-AD mice, a mouse model of AD that develops both amyloid and tau pathology, prior to the initial appearance of intraneuronal Ab (2 months of age). This work will provide mechanistic insight into the involvement of oligomeric Ab in the temporal and spatial progression of early AD pathogenic events and will potentially lead to the development of new anti-Ab therapeutics designed for early-stage intervention. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is an insidious neurodegenerative disorder that wields significant societal and economic impact. The development of more refined therapeutics directed at disease targets presently believed to be early mediators of the disease and their detailed assessment in state-of-the-art animal models will usher in a new class of therapeutics with the potential to be more than symptom-ameliorating, but truly disease course-modifying.